The present invention is related to a medicinal herbal composition for preventing or treating diabetes. The invention also relates to a method of preventing or treating diabetes by administering the composition to an individual.
Diabetes mellitus is a common, serious disease characterized by hyperglycemia. The disease can be divided into two major subclasses: insulin-dependent diabetes mellitus (IDDM), also known as type I diabetes, and non-insulin-dependent diabetes mellitus (NIDDM), also known as type II diabetes (World Health Organization Study Group. Diabetes mellitus. WHO Tech. Rep. Ser. 727:1-113, 1985). IDDM results from insulin deficiency caused by cell-mediated autoimmune destruction of pancreatic beta cells, and generally develops in the young (Yoon J W., Insulin-dependent diabetes mellitus. In: Roitt I M and Delves P J. (Eds.) Encyclopedia of Immunology, Second Edition. Academic Press Ltd., London, pp. 1390-1398, 1998; Bach J F., Insulin-dependent diabetes mellitus as a beta cell targeted disease of immunoregulation. J. Autoimm. 8:439-463, 1995). IDDM accounts for approximately 10-15% of the diabetic population worldwide (World Health Organization Study Group. Diabetes mellitus. WHO Tech. Rep. Ser. 727:1-113, 1985). In contrast, NIDDM results from a variable combination of insulin resistance and insulin deficiency, and generally develops in adults (Jun H S, et al., Pathogenesis of non-insulin-dependent (Type II) diabetes mellitus (NIDDM)xe2x80x94Genetic predisposition and metabolic abnormalities. Advanced Drug Delivery Reviews 35:157-177, 1999; DeFronzo R A., The triumvirate: xcex2-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 37:667-687, 1988). However, NIDDM can also develop at a younger age, as seen in the maturity-onset diabetes of the young (Pirart J., Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care 1:168-188, 1978). NIDDM accounts for over 85% of the diabetic population worldwide. Both IDDM and NIDDM can cause microvascular and macrovascular complications, resulting in increases in morbidity and mortality (Fajans S S, et al., Prediabetes, subclinical diabetes, and latent clinical diabetes: interpretation, diagnosis and treatment. In: Leibel D S, Wrenshall G S. (Eds.) On the Nature and Treatment of Diabetes. Excerpta Medica, Amsterdam, pp. 641-656, 1965).
NIDDM is a complex disease that is currently thought to be influenced by more than a single gene or environmental factor (Ghosh S, et al., Genetic analysis of NIDDM. Diabetes 45:1-14, 1995; Kobberling J. Studies on the genetic heterogeneity of diabetes mellitus. Diabetologia 7:46-49, 1971; Rotter J L, et al., Genetics of diabetes mellitus. In: Rifkin H, Porte D (Eds.) Diabetes Mellitus Theory and Practice. Elsevier, N.Y., pp. 378-413, 1990). Familial aggregation and the high concordance rate for the disease (60-100%) in identical twins suggest that genetic factors play an important role in the pathogenesis of NIDDM (O""Rahilly S, et al., Type 2 (noninsulin dependent) diabetes mellitus. New genetics for old nightmares. Diabetologia 31:407-414, 1988; Barnett A H, et al., Diabetes in identical twins. A study of 200 pairs. Diabetologia 20:87-93, 1981). In addition, environmental factors such as obesity, physical activity and diet also play a strong role in the development of the disease (Knowler W C, et al., Gm and type 2 diabetes mellitus: an association in American Indians with genetic admixture. Am. J. Hum. Genet. 43:520-526, 1988; Bennett P H, et al., Epidemiology and natural history of NIDDM: non-obese and obese. In: Alberti KGMM, DeFronzo R A, Keen H, Zimmett P (Eds.) International Textbook of Diabetes Mellitus. Wiley, N.Y., pp. 147-176, 1992; Helmrich S P, et al., Physical activity and reduced occurrence of NIDDM. N. Engl. J. Med 325:147-152, 1991). Although the relative contribution of genetic and environmental factors to the development of NIDDM differs among individuals, patients generally have two common metabolic abnormalities, insulin resistance and defects in glucose-stimulated insulin secretion, which lead to the disease state (Saad M F, et al., A two step model for development of non-insulin-dependent diabetes. Am. J. Med. 90:229-235, 1991; DeFronzo R A, et al., Pathogenesis of NIDDM: A balanced overview. Diabetes Care 15:318-368, 1992; Lillioja S, et al., Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 329:1988-1992, 1993).
The insensitivity of the target tissue in response to insulin (insulin resistance) appears to develop first in genetically predisposed subjects in the presence of the necessary environmental factors (Jun H S, et al., Pathogenesis of non-insulin-dependent (Type II) diabetes mellitus (NIDDM)xe2x80x94Genetic predisposition and metabolic abnormalities. Advanced Drug Delivery Reviews 35:157-177, 1999). To compensate for this, that is, to lower blood glucose and maintain normoglycemia, the secretion of insulin from the beta cells increases, resulting in hyperinsulinemia. Over time, the insulin resistance worsens, and the compensatory action fails, leading eventually to impaired glucose tolerance. Insulin secretion reaches a plateau, and beta cell function is impaired, resulting in insulin deficiency, and leading finally to hyperglycemic NIDDM. In addition, hyperglycemia itself leads to impaired insulin resistance and insulin secretion, exacerbating the disease.
The regulation of diet and exercise and/or treatment with insulin or hypoglycemia drugs have been used for the control of diabetes. Treatment with these agents is successful in some cases, but the mortality index continues to rise. Insulin treatment provides symptomatic relief rather than a cure for NIDDM. Hypoglycemic agents such as sulfonylureas and biguanides (metformin) also lower blood glucose, but again, simply provide symptomatic relief. Sulfonylureas lower the blood glucose level by stimulating the release of insulin from pancreatic beta cells. These agents directly stimulate insulin release by closing adenosyl triphosphate (ATP)-sensitive potassium channels and depolarizing the cell membrane (Aguilar-Bryan L, et al., Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268:423-426, 1995; Tan G H, et al., Pharmacologic treatment options for non-insulin-dependent diabetes mellitus. Mayo Clinic Proceedings 71:763-768, 1996; Lubbos H, et al., Oral hypoglycemic agents in type II diabetes mellitus. American Family Physician. 52:2075-2078, 1995) The side effects of sulfonylureas include hypoglycemia, renal and hepatic disease, gastrointestinal disturbances, increased cardiovascular mortality, dermatological reactions, dizziness, drowsiness and headache. Biguanides lower blood glucose levels by reducing intestinal glucose absorption and hepatic glucose, but not by stimulating insulin secretion. The major side effects of biguanidine are lactic acidosis and increased cardiovascular mortality. Alpha glucosidase inhibitors inhibit intestinal alpha glucosidases and consequently delay the digestion of sucrose and complex carbohydrates. The side effects of alpha glucosidase inhibitors include gastrointestinal side effects and hypoglycemia. Thiazolidinediones improve insulin resistance directly, enhancing the effects of circulating insulin, directly stimulate peripheral glucose uptake and inhibit glucose production in the liver. Thiazolidinediones are only effective in the presence of insulin and may cause red blood cell abnormalities, and headache.
Therefore, more effective drugs for the treatment of diabetes are clearly needed. We have long been interested in medicinal plants as a possible source for the development of hypoglycemic agents, and we have tried to halt the severe long-term complications of NIDDM in patients using extracts from various medicinal plants. We screened many plants and found that certain combinations of plant extracts have hypoglycemic effects. In particular, as exemplified infra, we discovered that the combined extracts, designated medicinal herbal compounds for treatment of type 2 diabetes (MHCTD), from Pterocarpus marsupium (Lodha R, et al. Traditional Indian systems of medicine. Ann. Acad. Med. Singapore 29:37-41, 2000; Sheehan E W,et al., A constituent of Pterocarpus marsupium, (xe2x88x92)-epicatechin, as a potential antidiabetic agent. J. Nat. Prod. 46:232-234, 1983; Manickam M, et al., Antihyperglycemic activity of phenolics from Pterocarpus marsupium. J. Nat. Prod. 60:609-610, 1997), Morus alba (Chen F, et al., Hypoglycemic activity and mechanisms of extracts from mulberry leaves (folium mori) and cortex mori radicis in streptozotocin-induced diabetic mice. Yakugaku Zasshi 115:476-482, 1995; Hikino H, et al., Isolation and hypoglycemic activity of moran A, a glycoprotein of Morus alba root barks. Planta Med. 2:159-160, 1985; Fukai T, et al., Structures of two natural hypotensive Diels-Alder type adducts, mulberrofurans F and G, from the cultivated mulberry tree (Morus lhou KOIDZ.). Chem Pharm Bull (Tokyo). 33:3195-3204, 1985; Nikaido T, et al., Inhibition of adenosine 3xe2x80x2,5xe2x80x2-cyclic monophosphate phosphodiesterase by phenolic constituents of mulberry tree. Chem. Pharm. Bull. (Tokyo). 32:4929-4934, 1984), Orthosiphon aristatus (Hsu H Y. Oriental Materia Medica: A Concise Guide. Oriental Healing Art Institute, Long Beach, Calif. p. 297), Opiophogon japonicus, Rosa rugosa, Commelina communis, Trichosanthis kirilowii and Anemarrhena asphodeloides (Ichik H, et al., New antidiabetic compounds, mangiferin and its glucoside. Biol. Pharm. Bull 21:1389-1390, 1998; Miura T, et al., Antidiabetic effect of seishin-kanro-to in KK-Ay mice. Planta Med. 63:320-322, 1997; Nakashima N, et al., Isolation of pseudoprototimosaponin AIII from rhizomes of Anemarrhena asphodeloides and its hypoglycemic activity in streptozotocin-induced diabetic mice. J. Nat. Prod. 56:345-350, 1993) showed a strong anti-diabetic effect in an animal model, the Goto-Kakizaki (GK) rat. In addition, treatment of NIDDM patients with the combined extracts for 3 months to 1 year significantly reduced blood glucose levels.
The present invention has met the hereinbefore described need.
An object of the invention is to provide a hypoglycemic effective composition comprising extracts from Pterocarpus marsupium, Morus alba, Orthosiphon aristatus, Opiophogon japonicus, Anemarrhena asphodeloides, or Trichosanthis kirilowii, in combination with extracts from Rosa rugosa and/or Commelina communis, and a pharmaceutically acceptable carrier thereof.
The extracts may be present in a relative ratio to each other of:
about 3% by weight to about 90% by weight of Pterocarpus marsupium, 
about 3% by weight to about 90% by weight of Morus alba, 
about 3% by weight to about 90% by weight of Orthosiphon aristatus, 
about 3% by weight to about 90% by weight of Opiophogon japonicus, 
about 3% by weight to about 90% by weight of Rosa rugosa, 
about 3% by weight to about 90% by weight of Commelina communis, 
about 3% by weight to about 90% by weight of Trichosanthis kirilowii, and
about 3% by weight to about 90% by weight of Anemarrhena asphodeloides. 
Preferably, the extracts may be present in a ratio of:
about 5% by weight to about 50% by weight of Pterocarpus marsupium, 
about 5% by weight to about 50% by weight of Morus alba, 
about 5% by weight to about 50% by weight of Orthosiphon aristatus, 
about 5% by weight to about 50% by weight of Opiophogon japonicus, 
about 3% by weight to about 50% by weight of Rosa rugosa, 
about 3% by weight to about 50% by weight of Commelina communis, 
about 3% by weight to about 50% by weight of Trichosanthis kirilowii, and
about 3% by weight to about 50% by weight of Anemarrhena asphodeloides. 
Still more preferably, the extracts may be present in a ratio of:
about 20% by weight of Pterocarpus marsupium, 
about 15% by weight of Morus alba, 
about 20% by weight of Orthosiphon aristatus, 
about 10% by weight of Opiophogon japonicus, 
about 8% by weight of Rosa rugosa, 
about 7% by weight of Commelina communis, 
about 10% by weight of Trichosanthis kirilowii, and
about 10% by weight of Anemarrhena asphodeloides. 
Another object of the invention is to provide the above composition, wherein the carrier is preferably a base of berries or fruit, a base of vegetable soup or bouillon, a soya-milk drink, or a nutritive supplement. In the case of using a base of berries or fruit, the base may be preferably made of extracts from Rosa canina, Vaccinum myrtillus and/or Vaccinum vitis-idea. In the case where the base is made of vegetable soup or bouillon, the base may be preferably made of extracts from Urtica diotica leaves, Allium cepa, and/or Ocimum sanctum. 
The composition above may further include extracts from Arctium lappa root, Eugenia jambolana seeds, Phaseus vulgaris husks, Trigonella foenum graeam seeds, and Vaccinum myrtillus leaves. Preferably, the extracts may be present in a ratio of:
about 5% by weight to about 20% by weight of Arctium lappa root,
about 5% by weight to about 70% by weight of Eugenia jambolana seeds,
about 5% by weight to about 20% by weight of Phaseus vulgaris husks,
about 10% by weight to about 30% by weight of Trigonella foenum graeam seeds, and
about 20% by weight to about 60% by weight of Vaccinum myrtillus leaves, wherein said ratio is relative to each of the extracts of Arctium lappa root, Eugenia jambolana seeds, Phaseus vulgaris husks, Trigonella foenum graeam seeds, and Vaccinum myrtillus leaves.
In another embodiment of the invention, the above composition may further comprise chromium, manganese, zinc, niacin, vitamin B6 or vitamin B12. In such a composition, the chromium may be present in an amount of about 20 to about 500 micrograms, manganese may be present in an amount of about 1 to about 10 milligrams, zinc may be present in an amount of about 2 to about 10 milligrams, niacin may be present in an amount of about 50 to about 500 milligrams, vitamin B6 may be present in an amount of about 1 to about 50 milligrams, and vitamin B12 may be present in an amount of about 5 to about 100 micrograms per dose.
Any of the above compositions may further comprise extracts from Acanthopanax, Schizandra, and optionally Rhodiola. Preferably, the extracts of Acanthopanax senticosus root, Schizandra chinensis fruit and seed, and Rhodiola rosea root are present in a ratio of about 4:2:1. An example of a Schizandra fixed combination is disclosed in Herbal Medicinal Product application nos. dnr 96-0045 and dnr 96-0046 before the Swedish Medical Product Agency, xe2x80x9cthe Swedish FDAxe2x80x9d. The contents of these applications are incorporated by reference herein in their entirety.
Another object of the invention is to provide a method of treating type II diabetes comprising administering to a person in need thereof an anti-diabetic or hypoglycemic effective amount of any of the above compositions.
In yet another object of the invention, a method of preventing onset of clinical type II diabetes is provided. The method comprises administering to a person in need thereof an anti-diabetic or hypoglycemic effective amount of any of the above compositions.
In still another object of the invention, a method of reducing blood glucose levels in patients who have blood glucose levels of about 200 to about 300 mg/dl at the beginning of treatment, is provided. The method comprises administering to the patient an effective amount of any of the above compositions.
In other embodiments, a method of increasing insulin secretion from pancreatic xcex2 cells, comprising administering an effective amount of any of the above compositions to a patient, is provided. A method of inhibiting degradation of complex carbohydrates to monosaccharides, comprising administering any of the above compositions to a patient, is also provided.
In another embodiment of the invention, this application provides for a hypoglycemic effective composition comprising extracts from Pterocarpus marsupium, Morus alba, Orthosiphon aristatus, Opiophogon japonicus, Anemarrhena asphodeloides, or a composition comprising extracts from Arctium lappa root, Eugenia jambolana seeds, Phaseus vulgaris husks, Trigonella foenum graeam seeds, and Vaccinum myrtillus leaves, in combination with extracts from Rosa rugosa and/or Commelina communis, and a pharmaceutically acceptable carrier thereof.